Smoking on the Brain

A scientist's search for the origins of addiction
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Perry’s Nut House is a roadside attraction on the central coast of Maine known for its collection of bizarre items: seahorse water pistols, a large stuffed albatross, exotic nut seeds. It closed in 1997 but reopened a year later, not long before David Perry, Ph.D., no relation to the owners, visited the shop during a road trip up the eastern coastline. He returned with a collection of bumper stickers, displaying the name of the shop. One now hangs above his desk. Another graces the door to his Neuropharmacology lab at The George Washington University Medical Center.

The Perry’s Nut House stickers have become something of an emblem for the lab. “You have to be a little nutty to be in science,” Perry explains. “People have to be quick on their feet, be willing to accept a little chaos and randomness. Nuttiness.”

For more than 10 years, this lab has been home to studies on the neurobiology of cigarette smoking, an addiction that Perry says is unmatched: “Heroin and cocaine are addictive drugs that take a terrible toll, but in terms of the sheer numbers of health problems, nicotine completely dwarfs them.” 

Perry, director of GW’s Pharmacology and Neuroscience graduate training program, is known for his research on the protein molecules at the surface of nerve cells that are activated by nicotine: nicotinic receptors. “He was one of the first people to work out exactly how to identify which subtype of nicotinic receptor you have in a certain tissue,” says Linda Werling, Ph.D., a close colleague and dean of Graduate Education at the Medical Center.

Within moments of taking a drag from a cigarette, a chain of events begins. As the lungs fill with smoke, nicotine races through the bloodstream and into the central nervous system. There, the chemical locks onto nicotinic receptors in regions throughout the brain. This binding often causes physiological changes in the nerve cells, opening channels and prompting signals to be sent from cell to cell. Nicotine docks to the same receptors as the neurotransmitter acetylcholine, which plays a role in breathing, learning, and memory. As these cells are stimulated, many of them release another neurotransmitter, dopamine, into the reward pathway of the brain, causing a rush of good feeling and energy.

“What nicotine seems to do is enhance the ability of a neuron to release its neurotransmitter,” Perry says. “The same amount of stimulus will cause more dopamine to be released if nicotine is present.” Over time, chronic smoking also causes the brain to sprout more nicotinic receptors, a phenomenon known as upregulation. This is believed to make the neurons more sensitive to the stimulant and increase its addictive characteristics.

More than 70 million people in the U.S. smoke cigarettes, and more than 20 percent of 12th graders and 12.3 percent of 10th graders have reported smoking, according to the National Institute on Drug Abuse. Those who begin smoking during adolescence may have the hardest time quitting, Perry says. Adolescence is a time of spectacular brain development. Synapses undergo a wild growth spurt followed by a pruning process: Brain connections that are used most are strengthened as the least-used are pruned away.

Perry’s focus on smoking during adolescence was piqued four years ago when a graduate student named Menahem Doura joined the lab. Doura wanted to integrate his previous work in genetics with the lab’s pharmacology focus, and liked the creative freedom of Perry’s lab. “He lets you be independ­ent,” Doura says. “He’s accessible but allows you to take the project in the directions you feel are the most interesting.”

Together, Perry and Doura designed an animal study to explore how chronic smoking affects the brain at different ages. They focused on genes in a small region of the midbrain where dopamine is produced, the ventral tegmental area. Since they weren’t studying specific genes, they knew they’d generate large amounts of data. A “shotgun approach,” Perry called it. But their research produced startling results.

The study treated one group of adolescent and one group of adult rats with nicotine for two weeks. Corresponding control groups were treated with saline. Four more groups were treated the same way but allowed an additional 30 days to withdraw from the nicotine.

Using DNA microarray analysis, Perry and Doura were able to determine which genes were activated by nicotine. They separated the gene response into three categories. Among the genes that turned on immediately, some turned off just as quickly and some remained changed for at least 30 days after the end of nicotine treatment. Still others were not affected immediately but by 30 days later had turned on.

Further, the adults and the adolescents demonstrated very different types of gene changes. The adult genes were more likely to be immediately or transiently affected. But the adolescent genes, they found, were much more likely to stay turned on longer or to have a delayed reaction. Says Perry: “The adolescent brain is in the process of developing, and nicotine affects that. So it’s doing something to the brain. It’s changing the development of your brain.”

There was another interesting twist. Many of the genes affected were involved in learning and memory. Perry suspects this is because nicotine structurally changes the brain in a way that makes adolescents who smoke more powerfully addicted than they would be if they had started smoking later in life. “The most striking feature that jumped out at me was, my God, the adolescents seem to have this delayed response or persistent response way more than the adults,” Perry says. “That fits with the idea that something changes in your brain, and then it’s more difficult to give it up.”

Many questions remain, he admits. Cells have tricky ways of sometimes shutting down RNA before it translates into its encoded protein so it’s unclear whether the DNA they’ve studied will make protein, or if the protein would be located in the same brain region.

Data like these, he adds, open up endless possibilities for more research. There are behavioral studies to test whether an animal exposed to nicotine as an adolescent desires it more as an adult. There are studies that would allow rats to self-administer their nicotine.

This last one is a better model for human smoking than the traditional osmotic mini-pump used to deliver nicotine, and the closest thing to a gold standard for addiction, Perry says. Using a lever system, animals could choose the amount of nicotine they want. The chemical would enter the brain as an occasional surge rather than a continuous flow.

There are also studies to be done on specific genes to better understand their function. “If we get a specific gene that looks interesting, we can go in and manipulate that gene and see if it changes their behavior,” he says. He suspects that a better understanding of these genes would offer insight into all kinds of addictive behavior and provide clues on how to help people quit.  

At the far end of his lab is a contraption that Perry calls a mad scientist’s dream. The device — made of Plexiglas tubes, needles, and superglue — measures the release of dopamine from cell tissue. He explains proudly how it was assembled, boxed up, and sent to him by a colleague. It’s a clumsy-looking contraption, but lab members report that it works better than more sophisticated versions. That is a source of pride for Perry; the fanciest isn’t always the best. And there is value here in the primitive, the homemade, the invention. The driving force behind the lab, after all, is just that: 

“It’s the thrill of the chase,” Perry says. “It’s exciting to find something new. That’s why we all do science when it comes down to it. We play around, and sometimes we find something new that no one’s found before.” 

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